Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a de novo, apparently balanced (2;8)(q35;q21.2) translocation in a boy with developmental delay and autism. Cross species (colour) paint (Rx) and SKY FISH, forward and reverse chromosome painting, and FISH with subtelomeric probes were used to examine the patient's karyotype, but further rearrangements were not detected. FISH with region specific clones mapping near 2q35 and 8q21.2 breakpoints and STS mapping performed on the isolated derivative chromosomes were used to refine the location of the breakpoints further. A cryptic deletion of between 4.23 and 4.41 Mb in extent and involving at least 13 complete genes or transcription units was found at the breakpoint on 2q35. The deletion includes the promoter and 5' untranslated region of the paired box 3 (PAX3) gene. The child has very mild dystopia canthorum which may be associated with the PAX3 haploinsufficiency. The 8q21.2 breakpoint is within MMP16 which encodes matrix metalloproteinase 16. We postulate that the cryptic deletion and rearrangement are responsible for the patient's phenotype and that a gene (or genes) responsible for autism lies at 2q35 or 8q21.2. The results present a step towards identifying genes predisposing to autism.
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PMID:A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation. 1207 Feb 44

To describe lifetime mental disorders among perpetrators of severe inter-personal crimes and to identify the problem domains most closely associated with aggression and a history of repeated violent criminality, we used structured interviews, clinical assessments, analyses of intellectual functioning, medical and social files, and collateral interviews in 100 consecutive subjects of pretrial forensic psychiatric investigations. Childhood-onset neuropsychiatric disorders [attention-deficit/hyperactivity disorder (AD/HD), learning disability, tics and autism spectrum disorders] affected 55% of the subjects and formed complex comorbidity patterns with adult personality disorders [including psychopathic traits according to the Psychopathy Checklist (PCL-R)], mood disorders and substance abuse. The closest psychiatric covariates to high Lifetime History of Aggression (LHA) scores and violent recidivism were the PCL-R scores and childhood conduct disorder (CD). Behavioral and affective PCL-R factors were closely associated with childhood AD/HD, CD, and autistic traits. The results support the notion that childhood-onset social and behavioral problems form the most relevant psychiatric symptom cluster in relation to pervasive adult violent behavior, while late-onset mental disorders are more often associated with single acts of violent or sexual aggression.
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PMID:Adult psychopathic personality with childhood-onset hyperactivity and conduct disorder: a central problem constellation in forensic psychiatry. 1467 46

Infection of the central nervous system by Borna disease virus (BDV) provides a unique model to study the mechanisms whereby a persistent viral infection can impair neuronal function and cause behavioral diseases reminiscent of mood disorders, schizophrenia, or autism in humans. In the present work, we studied the effect of BDV infection on the response of hippocampal neurons, the main target for this virus, to the neurotrophin BDNF. We showed that persistent infection did not affect neuronal survival or morphology. However, it blocked BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was abrogated, which resulted in severely impaired synaptogenesis and defects in synaptic organization. Thus, we provide the first evidence that a virus can interfere specifically with neurotrophin-regulated neuroplasticity, thereby hampering proper neuronal connectivity. These results may help to understand the behavioral disorders associated with BDV infection.
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PMID:Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. 1503 26

The objective of the study was to explore the possibility of common signs and symptoms of childhood-onset neuropsychiatric disorders and personality disorders, especially psychopathy, in a cohort of violent offenders. A structured neuropsychiatric status comprising features recorded in childhood-onset neuropsychiatric disorders and adult personality disorders was assessed in 89 perpetrators of severe crimes against other persons, analysed for factor structure, and compared to clinical diagnostics of neuropsychiatric disorders and independent assessments of psychopathy rated by the Psychopathy Checklist Revised (PCL-R). One or several childhood-onset neuropsychiatric disorders [autism, attention-deficit/hyperactivity disorder (AD/HD), tics and learning disability] affected the majority of adult offenders. A factor analysis yielded four higher-order problem constellations: Executive Dysfunction, Compulsivity, Social Interaction Problems and Superficiality. All four constellations were positively correlated with life histories of aggression, stressing the clinical importance of these problems in adult forensic psychiatry. Compulsivity and Social Interaction Problems were associated with autistic traits and tics, Executive Dysfunction with AD/HD, conduct disorder and psychopathic as well as autistic traits. Superficiality was a distinct aspect of AD/HD and psychopathic traits, especially the PCL-R factor reflecting interpersonal callousness. Neuropsychiatric disorders and personality disorders such as psychopathy share common symptoms. The various facets of psychopathy are associated with executive dysfunction and empathy deficits with superficial understanding of self, others and the rules of communication.
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PMID:Clinical neuropsychiatric symptoms in perpetrators of severe crimes against persons. 1619 25

There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
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PMID:A genetic variant that disrupts MET transcription is associated with autism. 1707 42

Autism is a common, severe and highly heritable neurodevelopmental disorder. The International Molecular Genetic Study of Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing in several independent multiplex samples and in two meta-analyses. Taking into account the location of the MET gene under this linkage peak, and the fact that it has recently been reported to be associated with autism, the gene was further analyzed as a promising autism candidate. The gene encodes a transmembrane receptor tyrosine kinase of the hepatocyte growth factor/scatter factor (HGF/SF). MET is best known as an oncogene, but its signalling also participates in immune function, peripheral organ development and repair, and the development of the cerebral cortex and cerebellum (all of which have been observed earlier as being disregulated in individuals with autism). Here we present a family-based association analysis covering the entire MET locus. Significant results were obtained in both single locus and haplotype approaches with a single nucleotide polymorphism in intron 1 (rs38845, P<0.004) and with one intronic haplotype (AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. Although these results failed to replicate in an independent sample of 82 Italian trios, the association itself was confirmed by a case-control analysis performed using the Italian cohort (P<0.02). The previously reported positive association of rs1858830 failed to replicate in this study. Overall, our findings provide further evidence that MET may play a role in autism susceptibility.
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PMID:MET and autism susceptibility: family and case-control studies. 1900 12

The ERK MAP kinase signaling cascade plays critical roles in brain development, learning, memory, and cognition. It has recently been appreciated that mutation or deletion of elements within this signaling pathway leads to developmental syndromes in humans that are associated with impaired cognitive function and autism. Here, we review recent studies that provide insight into the biological roles of the ERKs in the brain that may underlie the cognitive deficits seen in these syndromes.
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PMID:MAP'ing CNS development and cognition: an ERKsome process. 1918 60

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.
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PMID:Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. 1920 25

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior.
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PMID:Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. 1922 9

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5' promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.
Autism Res 2008 Jun
PMID:Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. 1936 Jun 63


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